Multimodal prehabilitation and postoperative outcomes in upper abdominal surgery: systematic review and meta-analysis

The impact of multimodal prehabilitation on postoperative complications in upper abdominal surgeries is understudied. This review analyzes randomized trials on multimodal prehabilitation with patient and hospital outcomes. MEDLINE, Embase, CINAHL, and Cochrane CENTRAL were searched for trials on prehabilitation before elective (non-emergency) abdominal surgery. Two reviewers independently screened studies, extracted data, and assessed study quality. Primary outcomes of interest were postoperative pulmonary complications (PPCs) and all-cause complications; secondary outcomes included hospital and intensive care length of stay. A meta-analysis with random-effect models was performed, and heterogeneity was evaluated with I-square and Cochran’s Q test. Dichotomous variables were reported in log-odds ratio and continuous variables were presented as mean difference. Ten studies (total 1503 patients) were included. Odds of developing complications after prehabilitation were significantly lower compared to various control groups (− 0.38 [− 0.75– − 0.004], P = 0.048). Five studies described PPCs, and participants with prehabilitation had decreased odds of PPC (− 0.96 [− 1.38– − 0.54], P < 0.001). Prehabilitation did not significantly reduce length of stay, unless exercise was implemented; with exercise, hospital stay decreased significantly (− 0.91 [− 1.67– − 0.14], P = 0.02). Multimodal prehabilitation may decrease complications in upper abdominal surgery, but not necessarily length of stay; research should address heterogeneity in the literature.


Search strategy
The search strategy was developed by a librarian specializing in systematic reviews (MF).On February 22, 2022, MF retrieved records from MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), and Cochrane CEN-TRAL, using filters for date range, human study RCTs, and exclusion of retracted material per best practices for Ovid interfaces 47 and CINAHL 48 .For a list of search strings used for each database, see Supplementary File: search strategy.

Inclusion and exclusion criteria
Studies were included according to the PICO (population, intervention, comparator, outcome) rubric 49 .The population of interest comprised adult patients with sarcopenia or frailty 50 undergoing elective (i.e., non-emergency) hepatopancreaticobiliary surgery, including exploratory laparotomy, pancreatectomy, distal pancreatectomy, pancreaticoduodenectomy, Whipple procedure, and pancreatic enucleation; elective abdominal surgeries; elective major abdominal surgeries; elective complex abdominal surgeries; elective abdominal oncologic surgeries; elective hepatobiliary surgery; open hepatectomies; open elective colon surgeries; and open elective gastric resection.Any mode of prehabilitation intervention was included-physical, nutritional, psychiatric, or other co-morbid condition optimization designed to improve recovery time-compared to patients not receiving prehabilitation in an RCT design.Non-RCTs were excluded to mitigate concerns regarding heterogeneity and bias which can occur in mixed-methods reviews 51 .Studies not reporting results relevant to our primary outcomes of interest, i.e., related to oxygenation or pulmonary function or other postoperative complication broadly construed (see below), were excluded (e.g., protocols).
Primary RCT reports from the year 2000 to search date were included with no language restriction.The date range was selected because rigorous primary studies on prehabilitation started in the early 2000s 52,53 , which is also when the concept of frailty had been most explicitly defined 50 .Peer-reviewed journal articles were included.Non-RCT study designs, unpublished work, technical reports, conference materials, and preprints were excluded.
After automated removal of duplicates using Covidence 54 , two reviewers (AD and FA) independently screened titles and abstracts for inclusion; these reviewers also assessed full text eligibility, using Covidence to streamline processing.Raters met for discussion as needed to assess disagreements and reach consensus at each step.

Data extraction
Data were collected on: setting (country) of study; study aim; period (dates, if reported); timing of prehabilitation (number of days/weeks before surgery, variations by treatment/comparator groups when relevant); population description (n-counts, inclusion/exclusion criteria) and demographics by group, including age, race/ethnicity, and gender; recruitment setting; modality of prehabilitation (physical therapy, nutritional therapy, psychosocial; anemia-related; respiratory therapy); primary and secondary outcome descriptions (retained for synthesis and meta-analysis if deemed feasible by the team's statistician, EH); and funding source and author declarations of potential conflicts of interest.For screening, two raters independently charted information and, using side-byside comparison of extractions in Covidence, met to form consensus.

Outcomes of interest
Our two primary outcomes of interest were PPCs and all-cause complications-inclusive of acute lung injury, postoperative pneumonia, or other postoperative pulmonary complications (aspiration, respiratory failure including hypoxic), non-invasive ventilation, unplanned intubation (re-intubation after postoperative extubation), and respiratory failure.Secondary outcomes included length of stay (LOS) in the hospital or intensive care unit (ICU).

Quality assessment
For risk of bias assessment, the JBI critical appraisal checklist for RCTs 55 was used.As for the screening process above, two raters independently applied the JBI instrument and then compared results and met for discussion to reach consensus, as facilitated by side-by-side comparison views in the Covidence platform.Studies were not excluded based on appraisal.In the case of prehabilitation studies, we anticipated that blinding participants and interventionalists would frequently and justifiably not be feasible.

Statistical analysis
Regarding effect measures for mortality, PPCs, and other complications, log-odds ratio is reported; for functional capacity, hospital LOS, and ICU LOS, mean difference is reported below.For continuous outcomes reported as median (IQR), we estimated mean and standard deviation following Wan et al. 56 .
For synthesis of each outcome, we report a table and a forest plot with summary statistics (log-odds ratio or mean difference) of each study and overall results.We performed a meta-analysis with random-effect models.Heterogeneity was evaluated with I-square (%) following Cochrane 57 , by which 0-40% can be interpreted as a possibly unimportant level of inconsistency; 30-60% as moderate heterogeneity; 50-90% as substantial heterogeneity; and 75-100% as considerable heterogeneity (ranges overlap as interpretation of meaningful inconsistency also depends upon factors such as effect size and direction as well as strength of evidence, e.g., P value).
Publication bias was evaluated with funnel plots for primary outcomes.Studies that fell outside of the 95% CI were considered as having potential bias.For certainty assessment, heterogeneity was evaluated with I-square.We performed subgroup analysis by stratifying prehab method (exercise vs. no exercise).When potential publication bias was detected, we performed sensitivity analysis by removing studies with potential publication bias.All statistical analysis was performed with Stata 16.1 (StataCorp LLC, College Station, Texas, USA).

Ethics declarations
Ethics committee review and participant consent are not applicable (literature review and meta-analysis); no trademarked drugs, chemicals, instruments, or other devices are discussed.

Search results
The initial search yielded 1167 distinct studies for screening, of which 96 articles underwent full-text review; 10 articles were selected for this systematic review [58][59][60][61][62][63][64][65][66][67] .Additionally, the references of the included studies were searched, and the team conducted forward searching (review of references found to have later cited our included articles); however, no additional articles met inclusion criteria (Fig. 1).

Results of quality assessment
A summary of quality assessment (Supplementary Figures S1, S2) found eight of the 10 included studies lacked the ability to blind participants and the treatment providers, as anticipated in a physical prehabilitation setting.Of more substantive concern, one study 66 did not blind the outcome assessors, while another 67 was unclear about randomization methods, allocation concealment, and blinding of the outcome assessors.Additionally, one study 60 had participant dissimilarities at baseline.
Hospital length of stay: The hospital LOS was an outcome of interest in all included studies.The model showed moderate heterogeneity (I 2 = 39.6%).The overall mean difference was − 0.48 between the prehabilitation group and the control group (− 1.34-0.38,P = 0.28; Fig. 5).Studies were subgrouped based on the prehabilitation methodology (exercise vs no exercise).In the exercise group, I 2 decreased to 15.5% and the LOS mean difference was significantly decreased by − 0.91 (− 1.67-− 0.14, P = 0.02; Fig. 6).In the no exercise group, I 2 decreased to ≈ 0.0% while the LOS mean difference was not significant 0.71 (− 0.33-1.74,P = 0.76).See also Supplementary Information for associated sensitivity analysis.

Discussion
Our systematic review analyzed 10 high-quality RCTs with a total of 1503 patients to assess the impact of prehabilitation on postoperative outcomes in patients undergoing major upper abdominal surgeries.
The major finding of the present study was the identification of lower odds of developing PPCs among the prehabilitation group with no significant heterogeneity as well as a decrease in all-cause complications.It should be emphasized that postoperative pulmonary complications are a well-known risk of major abdominal and/or gastrointestinal cancer operations.In a large, multi-center trial by Fernandez-Bustamante and colleagues 68 , the occurrence of even one such complication was associated with increased mortality, ICU admission, and length of stay.Apart from the morbidity, these complications are also associated with increased medical costs ranging between $26,000 and $48,000 US dollars in recent studies 69,70 .Many such studies call for the implementation of prehabilitation-oriented interventions to help reduce such healthcare burdens.While minimally invasive surgical approaches have demonstrated significant potential to further decrease PPCs, its implementation in complex gastrointestinal and cancer operations is still emerging 71,72 .Our aggregate conclusion that preoperative interventions appear to provide protective benefits against postoperative complications was generally consistent with the conclusions in the majority of research studies reviewed and analyzed.
Although we specifically used a uniquely narrowed definition of our intervention of interest to reduce heterogeneity based especially in the scope of abdominal studies, there is room for some comparison.In different aspects, our study population most closely resembles the meta-analyses by Hijazi et al. 38 (which included multiple   www.nature.com/scientificreports/modes of prehabilitation in major abdominal surgery, not restricted to RCTs) and Heger et al. 39 (restricted to RCTs exploring physical prehabilitation only).Our results support findings by Heger and colleagues that prehab and specifically exercise significantly reduces PPCs; however, our finding of lower all-cause complications in the prehabilitation group with moderate heterogeneity in the meta-analysis contrasts from Heger et al., who did not find significant reduction in all-cause complications.Notably, Hijazi and colleagues did not identify a difference in postoperative complications between prehabilitation and standard of care groups, likewise citing heterogeneity at multiple levels.Hughes and colleagues 35 examined patients undergoing major vascular and (laparoscopic) bariatric procedures, a major difference in population from our study, but similarly found a reduction in PPCs; the authors similarly selected data to reduce the heterogeneity and concluded that the potential postoperative benefits can be achieved with appropriate prehabilitation.
Our meta-analysis also examined hospital LOS, an outcome with moderate heterogeneity.Subgroup analysis comparing prehab exercise versus no exercise had a low heterogeneity (12-15%) with prehab patients demonstrating significantly lower hospital LOS (0.91 days).The no-exercise group did not have significant differences.Other systematic reviews demonstrate mixed results on hospital LOS, with one review focused on cancer patients showing encouraging results 41 while others on older adults (including but not limited to cancer patients) found no differences 35,40,42 .We likewise found no significant reduction in ICU LOS (moderate heterogeneity) despite the promising findings on lower PPCs.Since the need and subsequent length of stay can differ between clinical populations and procedures, these findings may be particularly sensitive to heterogeneity and require focused, population-specific attention (age and procedure-specific) and cautious generalization.
Although Canada, Europe and the UK, Australia and New Zealand, and Brazil were represented among the studies included in our systematic review, no articles were from the United States or other major geographical areas including the Asian and African continents, broadly indicating a paucity of evidence on and lack of global generalizability for prehabilitation and the need for additional setting-specific studies.

ERAS as a model
We concur with others that the field of prehabilitation needs standardization to reduce confounding and better distinguish benefits of specific interventions 73 and produce generalizable research results.Obvious parallels exist between prehab and ERAS programs 74,75 , and we conclude that the ERAS Society provides an ideal model for advocates of prehab programs to improve standardization.The ERAS Society has published standards for the development of future guidelines to ensure that established findings continue to apply across individual guidelines and that recommendations between guidelines are not contradictory.These guidelines employ champions from all aspects of the care team.Similar strategies could be employed in scaling prehabilitation programs.

Limitations
Despite inclusion of quality-assessed RCTs, our findings were limited by heterogeneity in the design, conduct, and reporting of the primary studies.We initially sought RCT reports with multimodal intervention modalities; however, most of the research focused on unimodal or bimodal prehab.We also discovered that frailty and sarcopenia were often omitted from the baseline characteristics among these studies, indicating a gap in reporting this salient feature which limited our ability to draw conclusions on our population of interest.We join other researchers 40 in encouraging future primary studies to track and report this important characteristic of surgical patients.Lastly, our review may be limited by the exclusion of non-RCTs, a methodological choice on which opinions have differed and evolved 51 ; future systematic review updates should consider inclusion of non-RCTs, particularly until additional, well-focused RCTs emerge in the literature.

Conclusion
Despite the limitations, our systematic review and meta-analysis uniquely focuses on prehabilitation in several ways.We included RCTs in patients who required major elective open abdominal surgery with consistent durations of prehabilitation between 8 days and 6 weeks.We found heterogeneity to be a limiting factor in collecting www.nature.com/scientificreports/data on outcomes, supporting the need for unified effort inclusive of all members of prehabilitation teams to standardize consensus protocols and statistical analysis.Prehab and ERAS programs should continue to function by identifying an at-risk population, implementing an evidence-based, personalized multimodal intervention, measuring the desired intervention benefits, and quantifying perioperative outcomes.Standardization of intermediate objective measures to quantify physiologic/physical responses to prehab are also needed.Lastly, while the current literature presents conflicted or weak support for prehab, we believe stratifying evidence-based components of prehab programs within specific disease sites, like the efforts of the ERAS Society, will reduce confounding and heterogeneity serving to create more generalizable results.Once prospective, disease-site specific prehab findings are available in a diversity of geographical settings, future meta-analyses will be able to support and validate potential bundled and multimodal prehabilitation care.

Figure 2 .
Figure 2. Intervention and outcome of interest of each study.

Figure 3 .
Figure 3. Forest plot showing pooled log odds ratio for pulmonary complication.

Figure 6 .
Figure 6.Forest plot showing pooled hospital LOS subgrouped by use of exercise method as prehabilitation.

Figure 7 .
Figure 7. Forest plot showing pooled ICU length of stay.

Table 1 .
General characteristics a of included studies.a For more extensive clinical characteristics and outcome measures, see Supplementary Information file: Included_studies_outcome_measures.xlsx.